Project 2 Summary The incidence and mortality of prostate cancer (PCa) is approximately 2 fold higher in African American (AA) than in European-American (EA) men, with AA men experiencing among the highest rates worldwide. Although environmental and socioeconomic factors play a role in PCa disparity, family history is a strong risk factor indicating that genetics also play a role. While allelic variation in genes involved in pathways relevant to PCa biology have been proposed as genetic cause or contributor for the increased PCa risk in AA men, genetic variation cannot adequately explain the phenotypic difference in PCa initiation and progression in AA and EA men, suggesting that epigenetic alterations such as differential DNA methylation and histone modification may explain the more aggressive clinical behavior of PCa in AA men. There is scientific evidence to suggest that aberrant DNA methylation and histone modification may contribute to prostate pathogenesis. However, most of the epigenetic research work has been carried out using EA samples with very little data on AA men. We have found significantly higher methylation in a small sample cohort of AA when compared to EA samples, suggesting that increase prevalence of epigenetic changes such as DNA methylation for several genes may affect AA men with PCa differently than EA men. The objective of this proposal is to identify genes that are epigenetically altered by differentially methylation in AA PCa that may explain the higher aggressiveness of AA PCa. Our hypothesis is that differential epigenetic alteration may represent an integration of lifestyle and genetic predisposing factors to create a more aggressive disease milieu in African American patients. Our study aims are to conduct: (1) Comprehensive Genome-wide assessment of DNA methylation and histone methylation/acetylation patterns in PCa from AA men; (2) Correlation analysis of transcriptome and epigenetic DNA methylation data in AA PCa; and (3) Evaluation of the biological activity of novel DNA methylated genes in PCa cell lines. The proposed work could produce several important outcomes. First, identification of genes regulated by DNA methylation changes in AA men could increase our understanding of the genetic changes contributing to aggressive nature of tumors among AA men and PCa disparity. Second, studies proposed here could lead to the identification of novel (?ethnic sensitive?) biomarkers that can predict disease aggressiveness and provide correlations between epigenetic changes and prostate tissue pathological features such as stage, grade and recurrence. Furthermore, because epigenetic DNA methylation changes are reversible, epigenetic drugs are being explored for reversing somatic epigenetic defects. Thus, studies could potentially lead to the identification of novel epigenetic targets for prostate cancer treatment. The successful outcome of this proposal will in the short term serve to fill in a gap that explains the role of epigenetic DNA methylation changes in contributing to higher aggressiveness of prostate cancer (PCa) in African-American (AA). In the long term, results will provide valuable insight into understanding the integration of environmental exposures and epigenetic predisposition to PCa disparity which fits with the mission of HU RCMI in addressing minority health disparities.